Anika Nagelkerke1,2, Fred C G J Sweep2, Hanneke Stegeman1, Reidar Grénman3, Johannes H A M Kaanders1, Johan Bussink1, Paul N Span1. 1. Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 2. Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 3. Department of Otorhinolaryngology-Head and Neck Surgery and Department of Medical Biochemistry, Turku University Hospital and University of Turku, Turku, Finland.
Abstract
BACKGROUND: The purpose of this study was to examine the hypoxic regulation of the PKR-like endoplasmic reticulum kinase (PERK)/activating transcription factor-4 (ATF4)/lysosome-associated membrane protein 3 (LAMP3)-arm of the unfolded protein response (UPR) in head and neck squamous cell carcinoma (HNSCC). METHODS: LAMP3 expression was determined in patient biopsies by immunohistochemistry and correlated to clinicopathological parameters. mRNA and protein expression for PERK, ATF4, and LAMP3 was evaluated after hypoxic exposure of HNSCC cell lines. RESULTS: In patients with HNSCC, high LAMP3 expression correlated with N classification (p = .019) and the occurrence of distant metastases during follow-up (p = .039). Patients with high LAMP3 levels had a worse metastasis-free survival (p = .008). Intriguingly, LAMP3 expression was localized exclusively in normoxic areas of tumors and xenografts. Expression of PERK, p-PERK, p-eIF2α, ATF4, and LAMP3 was not universally induced in hypoxic HNSCC cell lines. Exposure to endoplasmic reticulum-stress stimulated PERK, ATF4, and LAMP3 expression. CONCLUSION: LAMP3 is relevant for prognosis in HNSCC. However, the PERK/ATF4/LAMP3-arm of the UPR responds differently to hypoxia in HNSCC compared to other tumor types.
BACKGROUND: The purpose of this study was to examine the hypoxic regulation of the PKR-like endoplasmic reticulum kinase (PERK)/activating transcription factor-4 (ATF4)/lysosome-associated membrane protein 3 (LAMP3)-arm of the unfolded protein response (UPR) in head and neck squamous cell carcinoma (HNSCC). METHODS:LAMP3 expression was determined in patient biopsies by immunohistochemistry and correlated to clinicopathological parameters. mRNA and protein expression for PERK, ATF4, and LAMP3 was evaluated after hypoxic exposure of HNSCC cell lines. RESULTS: In patients with HNSCC, high LAMP3 expression correlated with N classification (p = .019) and the occurrence of distant metastases during follow-up (p = .039). Patients with high LAMP3 levels had a worse metastasis-free survival (p = .008). Intriguingly, LAMP3 expression was localized exclusively in normoxic areas of tumors and xenografts. Expression of PERK, p-PERK, p-eIF2α, ATF4, and LAMP3 was not universally induced in hypoxic HNSCC cell lines. Exposure to endoplasmic reticulum-stress stimulated PERK, ATF4, and LAMP3 expression. CONCLUSION:LAMP3 is relevant for prognosis in HNSCC. However, the PERK/ATF4/LAMP3-arm of the UPR responds differently to hypoxia in HNSCC compared to other tumor types.
Authors: Scott M Langevin; Damaris Kuhnell; Melissa A Orr-Asman; Jacek Biesiada; Xiang Zhang; Mario Medvedovic; Hala Elnakat Thomas Journal: RNA Biol Date: 2019-01-13 Impact factor: 4.652